CN102105148B - Therapeutic combination comprising an AURORA kinase inhibitor and antiproliferative agents - Google Patents
Therapeutic combination comprising an AURORA kinase inhibitor and antiproliferative agents Download PDFInfo
- Publication number
- CN102105148B CN102105148B CN2009801286342A CN200980128634A CN102105148B CN 102105148 B CN102105148 B CN 102105148B CN 2009801286342 A CN2009801286342 A CN 2009801286342A CN 200980128634 A CN200980128634 A CN 200980128634A CN 102105148 B CN102105148 B CN 102105148B
- Authority
- CN
- China
- Prior art keywords
- combination
- chemical compound
- proteasome inhibitor
- formula
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000001225 therapeutic effect Effects 0.000 title description 10
- 230000001028 anti-proliverative effect Effects 0.000 title description 2
- 229940123877 Aurora kinase inhibitor Drugs 0.000 title 1
- 239000003719 aurora kinase inhibitor Substances 0.000 title 1
- 239000003795 chemical substances by application Substances 0.000 title 1
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 229940125904 compound 1 Drugs 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 229940079156 Proteasome inhibitor Drugs 0.000 claims abstract description 19
- 239000003207 proteasome inhibitor Substances 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 34
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 17
- 229960001467 bortezomib Drugs 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 23
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 21
- 239000000651 prodrug Substances 0.000 abstract description 14
- 229940002612 prodrug Drugs 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000003102 growth factor Substances 0.000 abstract 2
- 229940043355 kinase inhibitor Drugs 0.000 abstract 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 15
- 108091000080 Phosphotransferase Proteins 0.000 description 14
- 102000020233 phosphotransferase Human genes 0.000 description 14
- 229960000397 bevacizumab Drugs 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 102000001253 Protein Kinase Human genes 0.000 description 9
- 108060006633 protein kinase Proteins 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 102000009465 Growth Factor Receptors Human genes 0.000 description 8
- 108010009202 Growth Factor Receptors Proteins 0.000 description 8
- 102000004584 Somatomedin Receptors Human genes 0.000 description 8
- 108010017622 Somatomedin Receptors Proteins 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 230000002062 proliferating effect Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 108090000461 Aurora Kinase A Proteins 0.000 description 4
- 102100032311 Aurora kinase A Human genes 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- NEPLDSFRUXZNGL-UHFFFAOYSA-N N1C=CC=C1.O1C(=CC(=O)C2=CC=CC=C12)C1=CC=CC=C1 Chemical compound N1C=CC=C1.O1C(=CC(=O)C2=CC=CC=C12)C1=CC=CC=C1 NEPLDSFRUXZNGL-UHFFFAOYSA-N 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229950002366 nafoxidine Drugs 0.000 description 4
- 238000011125 single therapy Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000005441 aurora Substances 0.000 description 3
- -1 bicyclic compound Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 208000009905 Neurofibromatoses Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 201000004931 neurofibromatosis Diseases 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 208000015768 polyposis Diseases 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 102000003989 Aurora kinases Human genes 0.000 description 1
- 108090000433 Aurora kinases Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- UUVZBXQNKNMKOQ-UHFFFAOYSA-N CN(CC1)CCN1c(cc1)ccc1C(NC(C(CC(CCCN)C(Cc1ccccc1)=O)=C)=N)=O Chemical compound CN(CC1)CCN1c(cc1)ccc1C(NC(C(CC(CCCN)C(Cc1ccccc1)=O)=C)=N)=O UUVZBXQNKNMKOQ-UHFFFAOYSA-N 0.000 description 1
- 241000459479 Capsula Species 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920000832 Cutin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003793 centrosome Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 201000007487 gallbladder carcinoma Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 230000001846 repelling effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention provides a combination comprising a compound 1 of formula (A) and one or more antineoplastic agents selected from the group consisting of an antibody inhibiting a growth factor or a receptor of the growth factor, a proteasome inhibitor or a derivative or prodrug thereof, and a kinase inhibitor or a derivative or prodrug thereof useful in the treatment of tumors.
Description
Technical field
The present invention relates generally to field of cancer, more specifically, provide a kind of anti-tumor compositions with collaborative anti-proliferative effect, comprise aurora inhibitors of kinases and the antibody and/or proteasome inhibitor and/or the inhibitors of kinases that suppress somatomedin.
Background technology
The dysfunction of protein kinase (PK) is the sign of a lot of diseases.Most of oncogene is all relevant with people's cancer coding of PK with proto-oncogene.The increased activity of PK also relates to a lot of nonmalignant diseases, for example benign prostatic hyperplasia, familial adenhomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell propagation, pulmonary fibrosis, arthritis, the glomerulonephritis relevant with atherosclerosis and the rear narrow and restenosis of performing the operation.
PK is also relevant with parasitic breeding with inflammatory diseases and virus.PK also brings into play Main Function in the pathogenesis of neurodegenerative disease with in occuring.
For the general reference of PK dysfunction or imbalance, referring to, Current Opinionin Chemical Biology for example, 1999,3,459-465.
Several kinases relevant with growth of cancer cells known in the art are Aurora As, particularly Aurora-2.
It is found that Aurora-2 overexpression in a lot of different tumor types.Comprise in breast carcinoma [Cancer Res.1999,59 (9), 2041-4] and the colon cancer in a lot of cancers, its gene mapping 20q 13 (chromosomal region) that is everlasting locates to increase.
Prognosis mala is relevant among the patient with breast cancer of 20q13 amplification and tumor-feminine gender, and Aurora-2 expresses increase and shows that prognosis mala also can reduce the time-to-live [J.Natl.Cancer Inst., 2002,94 (17), 1320-9] of bladder cancer patients.For the general reference of the effect of Aurora-2 in the centrosome dysfunction of cancer, also can be referring to Molecular CancerTherapeutics, 2003,2,589-595.
Several heterocyclic compounds known in the art are kinases inhibitors, wherein, having disclosed 3-formamido group-pyrazoles and 3-urea groups-pyrazoles and derivant thereof in International Patent Application WO 01/12189, WO12188, WO02/48114 and WO02/70515 is kinases inhibitor.
In WO 00/69846, WO 02/12242, WO 03/028720 and WO 03/97610, also disclosed the fused bicyclic compound that comprises the pyrazoles part and have kinase inhibiting activity.
Disclose, special nafoxidine also [3,4-c] pyrazole derivatives is the effective ATP-competitive inhibitor (Fancelli of Aurora A, D. wait the people: Journal ofMedicinal Chemistry.2005, vol.48, no.8, p.3080-3084.PCT/WO2005005427).
Astoundingly, have been found that, when with some antineoplastic agent combined administration, can strengthen above-mentioned nafoxidine also [3,4-c] antitumous effect of pyrazole derivatives, that is, particularly can delay proliferative disease process or treatment proliferative disease, particularly treat the tumor that other is known as the chemotherapeutic drug tolerance of antineoplastic agent.Especially, the antitumous effect of this combination is greater than the effect of separately using arbitrary combination members to reach, namely greater than only with a kind of effect that makes up member's single therapy.
Therefore, the invention provides the also new combination of [3,4-c] pyrazole derivatives and known drug of nafoxidine, this combination is particularly suitable for treating proliferative disease, especially cancer.More specifically, combination of the present invention is useful especially in treatment as antineoplastic agent, does not have Side effect, and the Side effect shortcoming relevant with the antineoplastic agent of current use just.
Summary of the invention
The invention provides a kind of therapeutic combination, it comprises the chemical compound 1 of (a) formula (A):
(b) one or more antineoplastic agents, described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors, wherein in each situation active component with free form or with the acceptable salt of its pharmacy or arbitrarily the form of hydrate exist.
The present invention also is provided for simultaneously, separates or use successively the combination preparation of combinations thereof.
The present invention also provides a kind of pharmaceutical composition that comprises combinations thereof, described combination also with pharmaceutically acceptable carrier, diluent or mixed with excipients.
The present invention also provides a kind of method for the treatment of proliferative disease, comprises the combinations thereof to patient's administering therapeutic effective dose that these needs are arranged.
The specific embodiment
In first embodiment, the invention provides a kind of therapeutic combination, it comprises the chemical compound 1 of (a) formula (A):
(b) one or more antineoplastic agents, described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors, wherein in each situation active component with free form or with the acceptable salt of its pharmacy or arbitrarily the form of hydrate exist.
In yet another aspect, combination of the present invention be for simultaneously, separately or the combination preparation that uses successively.
Another embodiment relates at the treatment proliferative disease or delays combination of the present invention in the method for process of proliferative disease, and wherein the method comprises to patient's while that these needs are arranged, uses successively or dividually this therapeutic combination.
In a further embodiment, the invention provides a kind of pharmaceutical composition, comprise therapeutic combination of the present invention and pharmaceutically acceptable carrier, diluent or mixed with excipients.
Another embodiment relates to the as defined above application of chemical compound 1 in the medicine of preparation treatment proliferative disease of formula (A), wherein said treatment comprises to the patient that these needs are arranged uses as defined above chemical compound 1 and one or more antineoplastic agents of formula (A) simultaneously, successively or dividually, and described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors.
The chemical compound 1 of formula (A) has chemical name N-{5-[(2R)-2-methoxyl group-2-phenylacetyl group]-Isosorbide-5-Nitrae, 5,6-nafoxidine is [3,4-c] pyrazole-3-yl also }-4-(4-methylpiperazine-1-yl) Benzoylamide.It can prepare described in WO2005/005427 (by with reference to being incorporated herein), has protein kinase inhibiting activity, therefore can be used as antineoplastic agent and is used for the treatment of.
The acceptable salt of pharmacy of the chemical compound of formula (A) comprises and inorganic or organic acid acid-addition salts, these acid for example are, nitric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propanoic acid, glycolic, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, methanesulfonic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Loprazolam, isethionic acid and salicylic acid etc.
Preferred embodiment according to the present invention, the antibody that suppresses somatomedin or growth factor receptors is selected from bevacizumab (antibody of VEGF), Cetuximab, Victibix, horse trastuzumab, Buddhist nun's trastuzumab (antibody of EGF-R ELISA), Herceptin and handkerchief trastuzumab (antibody of ErbB2).
Preferred embodiment according to the present invention, the antibody that suppresses somatomedin or growth factor receptors is bevacizumab.The bevacizumab conduct
Sell.
Proteasome inhibitor is the medicine of blocks protein enzyme body effect, and proteasome is the cell complexes of destroying protein.Preferred embodiment according to the present invention, proteasome inhibitor is bortezomib preferably.Bortezomib by Millennium Pharmaceuticals with
Selling, is the first human cytokines enzyme body inhibitor of testing in human body.It is approved for treatment relapsed multiple myeloma and mantle cell lymphoma in the U.S..
Preferred embodiment according to the present invention, inhibitors of kinases are the many or Dasatinibs of flavone pyrrole.
In the present invention, each active component of this combination is that amount with the collaborative antitumous effect of effective generation provides.
The present invention also provides a kind of is having this mammal that needs to comprise the method that alleviates the side effect that is caused by the antineoplaston that adopts antineoplastic agent among the people, the method comprises that amount with effective generation synergistic antitumor effect is to described administration combination preparation, described combination preparation comprises chemical compound and one or more antineoplastic agents of the formula (A) of above-mentioned definition, and described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors.
Term used herein " synergistic antitumor effect " refers to the combination by chemical compound 1 with one or more antineoplastic agents of the as defined above formula (A) of using effective dose to mammal (comprising the people), to suppress the growth of tumor, tumor is disappeared fully.Described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors.
Term used herein " combination preparation " is defined as " part of test kit " in a sense especially, as defined above combination partner (a) and (b) independently administration, perhaps use not commensurability combination partner (a) and the different fixed combination of (b), that is, simultaneously or in the different time points administration.Then for example use the component of the each several part of test kit while or time interleaving, that is to say, use any component of the each several part of test kit in different time points, with identical or different interval.Most preferably, the selection time interval so that be used in combination each several part to the therapeutic effect for the treatment of disease greater than only using combination partner (a) and any resulting therapeutic effect (b).In this combination preparation, the ratio of the combination partner of using (a) and the total amount of combination partner (b) can be different, for example for the needs of the satisfied patient subgroups that will treat or the needs of single patient, different needs can be depending on patient's disease specific, age, sex, body weight etc.Preferably, has at least a beneficial effect, for example jointly strengthen as combination partner (a) and effect (b), particularly synergy, for example, greater than the adduction effect, other beneficial effect, side effect is less, and toxicity is less, perhaps obtaining the effect of combined therapy under combination partner (a) and one or both non-effective dosage (b), particularly preferably is combination partner (a) and strong synergism (b).
Term administering used herein " refer to parenteral and/or Orally administered." parenteral " refers to intravenous, subcutaneous or intramuscular administration.
In the method for the invention, for the chemical compound 1 of using formula (A), the therapeutic process of normal operation is the 100mg/m by body surface area
2/ day-1500mg/m
2The scope of/day, continuous 21 days at most.More preferably, employed therapeutic process is the approximately 150mg/m by body surface area
2The 350mg/m of/Ri-Yue
2/ day, continuous 21 days at most.
In a particularly preferred scheme, the chemical compound of formula (A) is with 190 or 250mg/m of body surface area
2/ day dosage, the 1st day of three cycles and the 8th day infusion 3 hours.For example, in disclosed WO2008/052931 on May 8th, 2008 (by with reference to being incorporated herein) other possible therapeutic schemes are disclosed.
The chemical compound 1 of formula (A) can be used with various dosage forms, when for example Orally administered, with the form of tablet, capsule, sugar or thin membrane coated tablet, liquid solution or suspension; During rectal administration, with the form of suppository; When parenteral is used, for example with intramuscular, or pass through in vein and/or the sheath and/or the form of intraspinal injection or infusion.
In the method for the invention, for using proteasome inhibitor, preferred bortezomib, the therapeutic process of normal operation is per 3 all approximately 50mg/m
2-100mg/m
2Or 30mg/m weekly
2Above.
For the antibody of using the inhibition somatomedin, preferred bevacizumab, the therapeutic process of normal operation is 0.1mg/kg-100mg/kg.The therapeutic process that more preferably uses is the 1st day 1mg/kg-20mg/kg at 3 cycles.
For using inhibitors of kinases, preferred flavone pyrrole is many, and the therapeutic process of normal operation can be 0.1mg/kg-100mg/kg.The therapeutic process that more preferably uses is 1mg/kg-20mg/kg.
Antineoplaston of the present invention is particularly suitable for treating any type of cancer, include but not limited to: cancer, for example bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (comprising small cell lung cancer), esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma and skin carcinoma (comprising squamous cell carcinoma); The hematopoietic tumor of lymphatic system comprises leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, hodgkin's lymphoma, non Hodgkin lymphoma, mantle cell lymphoma, hair cell lymphoma and Burkett lymphoma; The hematopoietic tumor of myeloid lineage comprises acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; Multiple myeloma; The tumor in Interstitial cell source comprises fibrosarcoma and rhabdomyosarcoma; The tumor of maincenter and peripheral nervous system comprises astrocytoma, neuroblastoma, glioma and schwannoma; Other tumors comprise melanoma, spermocytoma, teratoma, osteosarcoma, xeroderma pigmentosum, cutin vitiligoidea (keratoxanthoma), capsula glandulae thyreoideae cancer and Kaposi sarcoma.
As mentioned above, the effect of combination of the present invention significantly strengthens, and toxicity does not have corresponding enhancing simultaneously.In other words, combined therapy of the present invention has strengthened the component (a) of the present invention's combination and/or the antitumous effect of component (b), has therefore obtained the most effective and the less tumor therapeuticing method of toxicity.
Pharmaceutical composition of the present invention can be used for anticancer therapy.
The present invention also provides a kind of commercial packing, in suitable case, comprise the chemical compound of (a) formula as defined above (A) and (b) one or more antineoplastic agents, described antineoplastic agent is selected from antibody, proteasome inhibitor or derivatives thereof or prodrug and inhibitors of kinases or derivatives thereof or the prodrug that suppresses somatomedin or growth factor receptors, wherein in each situation active component with free form or with the acceptable salt of its pharmacy or arbitrarily the form of hydrate exist, and be used for simultaneously, separately or the description of using successively.
In packing of the present invention, each component (a) is present in the single container device with (b) or in different cases.
Another embodiment of the invention is a kind of commercial packing, comprises aforesaid pharmaceutical composition or product.
Because the pivotal role of aurora kinase protein in regulating cell mitogen and propagation, combination of the present invention also can be used for the treatment of various cell proliferation disorders, for example, benign prostatic hyperplasia, familial adenhomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell propagation, pulmonary fibrosis, arthritis, the glomerulonephritis relevant with atherosclerosis and the rear narrow and restenosis of performing the operation.
Combination of the present invention also can be used for the treatment of cancer, viral infection, prevents AIDS generation, autoimmune disease and neurodegenerative disease in the individuality of infected by HIV as apoptotic regulator.
For example, shown the activity of combination of the present invention by following external and in vivo test, they are for explanation, and unrestricted the present invention.
Embodiment 1: the materials and methods of vitro cytotoxicity activity test
Inoculate human colon carcinoma (HCT-116) cell strain of exponential growth, and at 37 ℃ and moist 5%CO
2Cultivate under the atmosphere.In the experiment culture medium, add medicine, and in the dark 37 ℃ of lower cultivations 72 hours.Add chemical compound 1 and the antineoplastic agent of formula (A) of the above-mentioned definition of several dosage after 24 hours in this culture medium in inoculation.Test successively application program (use another kind of medicine after 24 hours administered compound 1).Preparing before use drug solution.When treatment finishes, by adenosine triphosphate monitoring system (CellTiterGlo-Promega) in the cell, use Envision (PerkinElmer) to measure cell proliferation as reader.Estimate inhibition with the data of AssayExplorer (MDL) program comparision treatment group and matched group active.Calculate the dosage that suppresses 50% Growth of Cells with S type interpolation curve.Based on Chou-Talalay equation (the Adv Enzyme Regul 1984 that is used for not repelling mutually medicine; 22:27-55), come calculation combination index (C.I.) with the computer program that is used for the multi-medicament effect analysis, wherein C.I.＜1 expression is greater than the adduction effect (C.I.＞strong antagonism of 3 expressions; 1.3＜C.I.＜3, the expression antagonism; 0.8＜C.I.＜1.3, the expression adduction; 0.3＜C.I.＜0.8, the expression synergism; C.I.＜0.3, the strong synergism of expression).
Embodiment 2: active with the vitro cytotoxicity of flavone pyrrole combination how
Result shown in the table 1 shows, for human colon carcinoma HCT-116 cell strain, combined administration chemical compound 1 has been given birth to the synergistic antitumor effect with flavone pyrrole fecund.
Table 1
Embodiment 3: render a service with the anti-tumor in vivo of the combination of monoclonal antibody bevacizumab
Will be from the Balb of Harlan (Italy), the Nu/Nu male mice remains in the cage with the filter paper covering, with food and the tool sterilization of sleeping, and with the water acidify.Subcutaneous injection 2.5x10 in nude mice
6Individual DU145 prostate gland cancer cell (from American Type CultureCollection).Selecting this tumor model is because before verified, and bevacizumab suppresses angiogenesis and growth (referring to list of references: The Prostate 36:1-10,1998) in vivo in the model.When all groups of weighing with the tumor instrument of weighing all be 0.15g when being the tumor tangibly, injecting tumor cell begin treatment after 9 days.According to the known stability of chemical compound, only preparation before facing treatment of bevacizumab, chemical compound 1 is preparation every day.
The from the 9th to 17 day, totally 9 days, with the volume of 10ml/kg, the dosage of 15mg/kg, every day 2 times (BID) was by abdominal channels administered compound 1.The 9th, 13,17 days volumes with 10ml/kg behind tumor cell injection, the dosage intraperitoneal of 20mg/kg is used bevacizumab.When combined administration, the 9th, 10,11,12,13,14,15,16,17,18 and 19 days administered compounds 1 the 9th, 13, are used bevacizumab behind 17 days administered compounds 1 immediately.Measured tumor growth and body weight in per 3 days.Estimate tumor growth by caliper.Record two diameters, calculate tumor weight according to following formula: length (mm) * width
2/ 2.With the effect of estimating antineoplaston that postpones the growth of tamor index formula (referring to list of references: Anticancer drugs 7:437-60,1996).Delay (T-C value) is defined as treatment group (T) and matched group (C) reaches the required time difference of pre-sizing (1g) (unit: the sky).Based on losing weight to estimate toxicity.Report the test is in following table 2.Chemical compound 1 has produced obvious adduction/synergy with the combined administration of bevacizumab: the T-C that chemical compound 1 is observed during with the bevacizumab combination is better than the simple adduction of the T-C that the single therapy of expection obtains.In any treatment group, all do not observe toxicity.
Table 2
* the 9th, 10, intraperitoneal was treated 2 times in 11,12,13,14,15,16,17,18 and 19 days.
* is the 9th, 13, and intraperitoneal was treated in 17 days.
* * the 9th, 13,17 days, bevacizumab treatment; The 9th, 10,11,12,13,14,15,16,17,18 and 19 days, chemical compound 1 treatment
Embodiment 4: render a service with the anti-tumor in vivo of the combination of bortezomib
To remain in from the SCID male mice of Harlan (Italy) in the cage with the filter paper covering, with food and the tool sterilization of sleeping, and with the water acidify.Subcutaneous injection 5x10 in the SCID mice
6Individual HL-60 people's acute myeloid leukemia cells in children (from American Type CultureCollection).Select this model to be because before verified, chemical compound 1 suppresses this model growth in vivo, also is based on this model as the application of the representative of haematol malignant tumor simultaneously.
When the tumor tangibly, at injection tumor cell begin treatment after 12 days.According to the known stability of chemical compound, bortezomib is preparation before facing treatment, and chemical compound 1 is preparation every day.
With the volume of 10ml/kg, the dosage of 15mg/kg, every day 2 times (BID), by abdominal channels administered compound 1, totally 12 days (12-23 days).Behind tumor cell injection the 12nd, 16,20 and 24 days, with the volume of 10ml/kg, the dosage of 0.5mg/kg is used bortezomib by intravenous route; In addition, behind tumor cell injection the 12nd, 16,20 and 24 days are to use bortezomib with the volume of 10ml/kg, the dosage of 1mg/kg by intravenous route.When combined administration, in the interval of bortezomib for treating, namely the 13rd, 14,15,17,18,19,21,22,23,25,26 and 27 days administered compounds 1.Measured tumor growth and body weight in per 3 days.Estimate tumor growth by caliper.Record two diameters, calculate tumor weight according to following formula: length (mm) * width
2/ 2.With the effect of estimating antineoplaston that postpones the growth of tamor index formula (referring to list of references: Anticancer drugs7:437-60,1996).Delay (T-C value) is defined as treatment group (T) and matched group (C) reaches the required time difference of pre-sizing (1g) (unit: the sky).Based on losing weight to estimate toxicity.Report the test is in following table 3.Chemical compound 1 has produced obvious adduction/synergy with the combined administration of the bortezomib of 0.5mg/kg: the T-C that observes during the bortezomib combination of chemical compound 1 and 0.5mg/kg is better than the simple adduction of the T-C that the single therapy of expection obtains.In any treatment group, all do not observe toxicity.Chemical compound 1 has produced strong synergy with the combined administration of the bortezomib of 1mg/kg: the T-C (35.7) that observes when the bortezomib of chemical compound 1 and 1mg/kg makes up is significantly better than the simple adduction (17.3) of the T-C of the single therapy acquisition of expection.In treatment group, observe the sign of some toxicity.
Table 3
* the 12nd, 13,14,15,16,17,18,19,20,21, intraperitoneal treatment in 22,23 days 2 times.
* is the 12nd, 16, treats by intravenous route in 20,24 days.
* * is the 12nd, 16,20,24 days bortezomib for treating, and the 13rd, 14,15,17,18,19,21,22,23,25, chemical compound 1 treatment in 26 and 27 days.
Claims (5)
1. combination preparation comprises the chemical compound 1 of (a) formula (A) and (b) proteasome inhibitor, and wherein said proteasome inhibitor is bortezomib,
Wherein in each situation, each active component of this combination preparation exists with free form or with the form of the acceptable salt of its pharmacy.
2. according to claim 1 combination preparation, its be for simultaneously, separately or the combination preparation that uses successively.
3. pharmaceutical composition comprises the chemical compound 1 of (a) formula (A) and (b) proteasome inhibitor and pharmaceutically acceptable carrier, diluent or excipient, and wherein said proteasome inhibitor is bortezomib,
4. the chemical compound 1 of (a) formula (A) and (b) proteasome inhibitor is for the preparation for the treatment of cancer or delaying application in the medicine of process of cancer, wherein said proteasome inhibitor is bortezomib,
5. commercial package, in suitable case, comprise the chemical compound 1 of (a) formula (A) and (b) proteasome inhibitor and be used for simultaneously, separately or the description of using successively, wherein active component exists with free form or with the form of the acceptable salt of its pharmacy in each situation, wherein said proteasome inhibitor is bortezomib
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8323608P | 2008-07-24 | 2008-07-24 | |
| US61/083,236 | 2008-07-24 | ||
| PCT/EP2009/058779 WO2010009985A2 (en) | 2008-07-24 | 2009-07-09 | Therapeutic combination comprising an aurora kinase inhibitor and antiproliferative agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102105148A CN102105148A (en) | 2011-06-22 |
| CN102105148B true CN102105148B (en) | 2013-04-10 |
Family
ID=41131833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801286342A Expired - Fee Related CN102105148B (en) | 2008-07-24 | 2009-07-09 | Therapeutic combination comprising an AURORA kinase inhibitor and antiproliferative agents |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20110129467A1 (en) |
| EP (1) | EP2313097B1 (en) |
| JP (1) | JP5683462B2 (en) |
| CN (1) | CN102105148B (en) |
| AR (1) | AR072806A1 (en) |
| ES (1) | ES2415907T3 (en) |
| HK (1) | HK1154342A1 (en) |
| TW (1) | TW201008945A (en) |
| WO (1) | WO2010009985A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2701708T3 (en) * | 2011-04-29 | 2020-11-02 | The Penn State Research Foundation | Small molecule trail gene induction by normal and tumor cells as an anticancer therapy |
| WO2019161000A1 (en) * | 2018-02-15 | 2019-08-22 | Children's Hospital Medical Center | Methods for treating fibrosis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820009A (en) * | 2003-07-09 | 2006-08-16 | 法玛西雅意大利公司 | Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9911053D0 (en) | 1999-05-12 | 1999-07-14 | Pharmacia & Upjohn Spa | 4,5,6,7-tetrahydroindazole derivatives process for their preparation and their use as antitumour agents |
| PL353455A1 (en) | 1999-08-12 | 2003-11-17 | Pharmacia Italia S.P.A. | 3(5)-amino-pyrazole derivatives, process for their preparation and their use as antitumor agents |
| KR100904157B1 (en) | 2000-08-10 | 2009-06-23 | 파마시아 이탈리아 에스.피.에이. | Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| EP1345909A1 (en) | 2000-11-27 | 2003-09-24 | Pharmacia Italia S.p.A. | Phenylacetamido-pyrazole derivatives and their use as antitumor agents |
| WO2002070515A2 (en) | 2001-01-26 | 2002-09-12 | Pharmacia Italia Spa | Chromane derivatives, process for their preparation and their use as antitumor agents |
| CZ2004359A3 (en) | 2001-09-26 | 2004-09-15 | Pharmacia Italia S.P.A. | Aminoindazole derivatives exhibiting kinase inhibitor activity, process of their preparation and pharmaceutical compositions in which the derivatives are comprised |
| WO2003097610A1 (en) | 2002-05-17 | 2003-11-27 | Pharmacia Italia S.P.A. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| MX2007005155A (en) * | 2004-10-29 | 2007-06-26 | Banyu Pharma Co Ltd | Novel aminopyridine derivatives having aurora a selective inhibitory action. |
| AU2006315334B2 (en) * | 2005-11-16 | 2011-05-19 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
| WO2007090794A1 (en) * | 2006-02-10 | 2007-08-16 | Nerviano Medical Sciences S.R.L. | Combinations comprising a cdk inhibitor and a growth factor antibody or anti-mitotic |
| TW200808311A (en) * | 2006-03-30 | 2008-02-16 | Nerviano Medical Sciences Srl | Use of a kinase inhibitor for the treatment of particular resistant tumors |
| GB0609619D0 (en) * | 2006-05-16 | 2006-06-21 | Astrazeneca Ab | Combination |
| JP2008081492A (en) * | 2006-08-31 | 2008-04-10 | Banyu Pharmaceut Co Ltd | New aminopyridine derivative having aurora a selective inhibitory action |
| WO2008094321A2 (en) * | 2006-10-04 | 2008-08-07 | Universtiy Of South Florida | Akt sensitization of cancer cells |
| EA200970444A1 (en) | 2006-11-03 | 2009-12-30 | НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. | METHOD OF INTRODUCTION OF ANTI-TUMOR COMPOUND |
| AR063581A1 (en) * | 2006-11-08 | 2009-02-04 | Schering Corp | IMIDAZOPIRAZINS AS INHIBITORS OF PROTEIN QUINASA |
| WO2012000188A1 (en) | 2010-06-30 | 2012-01-05 | Tot Shanghai Rd Center Co., Ltd. | Recombinant tumor vaccine and method of producing such |
-
2009
- 2009-07-09 JP JP2011519108A patent/JP5683462B2/en not_active Expired - Fee Related
- 2009-07-09 WO PCT/EP2009/058779 patent/WO2010009985A2/en active Application Filing
- 2009-07-09 EP EP09780399A patent/EP2313097B1/en not_active Not-in-force
- 2009-07-09 US US13/054,868 patent/US20110129467A1/en not_active Abandoned
- 2009-07-09 CN CN2009801286342A patent/CN102105148B/en not_active Expired - Fee Related
- 2009-07-09 ES ES09780399T patent/ES2415907T3/en active Active
- 2009-07-15 AR ARP090102682A patent/AR072806A1/en unknown
- 2009-07-23 TW TW098124836A patent/TW201008945A/en unknown
-
2011
- 2011-08-12 HK HK11108473.6A patent/HK1154342A1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820009A (en) * | 2003-07-09 | 2006-08-16 | 法玛西雅意大利公司 | Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2313097B1 (en) | 2013-03-27 |
| EP2313097A2 (en) | 2011-04-27 |
| US20110129467A1 (en) | 2011-06-02 |
| JP2011528682A (en) | 2011-11-24 |
| HK1154342A1 (en) | 2012-04-20 |
| WO2010009985A3 (en) | 2010-04-22 |
| TW201008945A (en) | 2010-03-01 |
| WO2010009985A2 (en) | 2010-01-28 |
| CN102105148A (en) | 2011-06-22 |
| JP5683462B2 (en) | 2015-03-11 |
| AR072806A1 (en) | 2010-09-22 |
| ES2415907T3 (en) | 2013-07-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102105152B (en) | Therapeutic combination comprising a cdks inhibitor and an antineoplastic agent | |
| KR101098061B1 (en) | / 6474 use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability | |
| EP2435041B1 (en) | Therapeutic combination comprising a PLK1 inhibitor and an antineoplastic agent | |
| JP2014132009A5 (en) | ||
| JP2012500180A5 (en) | ||
| CN101355936B (en) | Combinations comprising a CDK inhibitor and a growth factor antibody or anti-mitotic | |
| CN104997808A (en) | Method and compositions for treatment of cancer | |
| CN102753176B (en) | Therapeutic combination comprising a cdc7 inhibitor and an antineoplastic agent | |
| TWI641374B (en) | Antineoplastic agent containing low-dose irinotecan hydrochloride hydrate | |
| CN102105148B (en) | Therapeutic combination comprising an AURORA kinase inhibitor and antiproliferative agents | |
| CN102105147B (en) | Therapeutic combination comprising an AURORA kinase inhibitor and an antineoplastic agent | |
| WO2024137778A1 (en) | Cancer treatments using mta-cooperative prmt5 inhibitors | |
| CN102448454B (en) | Comprise the Therapeutic combinations of PLK1 inhibitor and antitumor agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1154342 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1154342 Country of ref document: HK |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130410 Termination date: 20210709 |